Figure 1.

Neuropathophysiology of PKU. Decreased PAH activity results in hyperphenylalaninemia as well as hypotyrosinemia. The high Phe levels further restrict transport of tyrosine across the blood–brain barrier, as well as impairing tyrosine and tryptophan hydroxylase systems, as well as cholesterol synthesis, creating a hypomonoaminergic state in the brain, predominantly in frontal and limbic circuits where these neurotransmitters predominate. There is also reduced glutamatergic neurotransmission, which results in reduced synaptic plasticity, and in turn atrophy. Myelination is critically affected by high Phe levels, which impair protein synthesis, as well as switch oligodendrocytes to an “off” or non-myelinating state.